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Background & Aims: Oncogenic Kras G12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM), an actin-based morphogenetic process, and drives pancreatic ductal adenocarcinoma (PDAC). mTOR (mechanistic target of rapamycin kinase) complex 1 (mTORC1) and 2 (mTORC2) contain Rptor and Rictor, respectively, and are activated downstream of Kras G12D , thereby contributing to PDAC. Yet, whether and how mTORC1 and mTORC2 impact on ADM and the identity of the actin nucleator(s) mediating such actin rearrangements remain unknown., Methods: A mouse model of inflammation-accelerated Kras G12D -driven early pancreatic carcinogenesis was used. Rptor, Rictor, and Arpc4 (actin-related protein 2/3 complex subunit 4) were conditionally ablated in acinar cells to deactivate the function of mTORC1, mTORC2 and the actin-related protein (Arp) 2/3 complex, respectively., Results: We found that mTORC1 and mTORC2 are markedly activated in human and mouse ADM lesions, and cooperate to promote Kras G12D -driven ADM in mice and in vitro. They use the Arp2/3 complex as a common downstream effector to induce the remodeling the actin cytoskeleton leading to ADM. In particular, mTORC1 regulates the translation of Rac1 (Rac family small GTPase 1) and the Arp2/3-complex subunit Arp3, whereas mTORC2 activates the Arp2/3 complex by promoting Akt/Rac1 signaling. Consistently, genetic ablation of the Arp2/3 complex prevents Kras G12D -driven ADM in vivo. In acinar cells, the Arp2/3 complex and its actin-nucleation activity mediated the formation of a basolateral actin cortex, which is indispensable for ADM and pre-neoplastic transformation., Conclusions: Here, we show that mTORC1 and mTORC2 attain a dual, yet nonredundant regulatory role in ADM and early pancreatic carcinogenesis by promoting Arp2/3 complex function. The role of Arp2/3 complex as a common effector of mTORC1 and mTORC2 fills the gap between oncogenic signals and actin dynamics underlying PDAC initiation., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Intraductal papillary mucinous neoplasias (IPMNs) are precancerous cystic lesions that can develop into pancreatic ductal adenocarcinomas (PDACs). These large macroscopic lesions are frequently detected during medical imaging, but it is unclear how they form or progress to PDAC. We aimed to identify cells that form IPMNs and mutations that promote IPMN development and progression., Methods: We generated mice with disruption of Pten specifically in ductal cells (Sox9CreER T2 ;Pten flox/flox ;R26R YFP or Pten ΔDuct/ΔDuct mice) and used Pten ΔDuct/+ and Pten +/+ mice as controls. We also generated Kras G12D ;Pten ΔDuct/ΔDuct and Kras G12D ;Pten ΔDuct/+ mice. Pancreata were collected when mice were 28 weeks to 14.5 months old and analyzed by histology, immunohistochemistry, and electron microscopy. We performed multiplexed droplet digital polymerase chain reaction to detect spontaneous Kras mutations in Pten ΔDuct/ΔDuct mice and study the effects of Ras pathway activation on initiation and progression of IPMNs. We obtained 2 pancreatic sections from a patient with an invasive pancreatobiliary IPMN and analyzed the regions with and without the invasive IPMN (control tissue) by immunohistochemistry., Results: Mice with ductal cell-specific disruption of Pten but not control mice developed sporadic, macroscopic, intraductal papillary lesions with histologic and molecular features of human IPMNs. Pten ΔDuct/ΔDuct mice developed IPMNs of several subtypes. In Pten ΔDuct/ΔDuct mice, 31.5% of IPMNs became invasive; invasion was associated with spontaneous mutations in Kras. Kras G12D ;Pten ΔDuct/ΔDuct mice all developed invasive IPMNs within 1 month. In Kras G12D ;Pten ΔDuct/+ mice, 70% developed IPMN, predominately of the pancreatobiliary subtype, and 63.3% developed PDAC. In all models, IPMNs and PDAC expressed the duct-specific lineage tracing marker yellow fluorescent protein. In immunohistochemical analyses, we found that the invasive human pancreatobiliary IPMN tissue had lower levels of PTEN and increased levels of phosphorylated (activated) ERK compared with healthy pancreatic tissue., Conclusions: In analyses of mice with ductal cell-specific disruption of Pten, with or without activated Kras, we found evidence for a ductal cell origin of IPMNs. We also showed that PTEN loss and activated Kras have synergistic effects in promoting development of IPMN and progression to PDAC., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The effects of pancreatic duct ligation on the digestion and absorption of a randomly 14C-labeled protein meal has been investigated in the rat. Although there was a significant reduction in luminal digestion and absorption of the protein meal in the pancreatic duct-ligated animals compared with controls, 37% of administered protein was absorbed despite absence of luminal pancreatic proteolytic enzyme activity. To characterize further the digestive and absorptive processes that occur in the absence of luminal pancreatic proteolytic enzyme activity, whole protein meal (untreated) and protein preincubated with (1) pepsin and HCl, and (2) HCl alone (treated), was instilled into isolated loops of rat intestine containing no demonstrable pancreatic proteolytic enzyme activity. Thirty per cent absorption of the untreated protein meal occurred in 4 hr; significantly greater amounts of both treated forms of meal were absorbed. It is concluded that the small bowel has the capacity to hydrolyze and absorb nutritionally significant amounts of dietary large molecular weight protein in the absence of luminal pancreatic enzyme activity. Furthermore, this process may be enhanced by prior denaturation and proteolysis in the stomach.